Project Summary Glioblastoma (GBM), the most common primary brain tumor, has median patient survival of little more than one year. Surgical resection of all enhancing tumor prolongs survival, yet successful resection is challenging because GBM tumors diffusely infiltrate the brain, which results in >90% local recurrence. Development of a next-generation fluorescent molecular imaging agent to help surgeons differentiate cancerous from normal tissue intraoperatively will help reduce the rate of local recurrence and improve patient survival outcomes. No such agent for guided surgical resection of GBM currently has US FDA approval. An extracellular fragment of the cell surface adhesion molecule PTP is a unique imaging biomarker of the tumor microenvironment. The PTP fragment arises from proteolytic cleavage of the receptor protein tyrosine phosphatase (PTP), a proteolysis seen in multiple tumor types including GBM. An agent that binds to this PTP fragment, SBK2, recognizes human GBM tumors. Systemic delivery of the SBK2 agent results in binding to tumor cells within minutes in orthotopic xenografts in rodents, and can label virtually all the dispersing brain tumor cells several millimeters away from the main tumor mass in mouse brains in vivo. This proposal aims to translate this highly-selective fluorescent SBK2 agent for pre-surgical systemic delivery to cancerous GBM tissue and render it visible in real-time by current surgical microscopy adapted with standard fluorescent filters. The fluorescent SBK2 molecular imaging agent would enhance the efficacy and efficiency of GBM surgery by allowing real-time decisions regarding tumor borders. In this Academic-Industrial Partnership, a team with expertise in molecular biology, neurosurgery and molecular imaging regulatory approval, will work together to translate SBK2 from a preclinical to a clinical agent. To achieve this goal, the team will need to perform cGMP synthesis and toxicology studies before obtaining FDA regulatory approval for investigational use. Upon FDA approval, the cGMP SBK2 agents will be tested in a Phase 0 eIND imaging trial during surgical resection of GBM for determination of safety profile and imaging efficacy. We expect that this translational plan for the SBK2 imaging agent will yield a new clinical imaging capability for surgeon end users to reduce tumor burden and prolong patient survival.